NM_004380.3:c.5039_5041delCCT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_004380.3(CREBBP):c.5039_5041delCCT(p.Ser1680del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CREBBP
NM_004380.3 disruptive_inframe_deletion
NM_004380.3 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
Publications
19 publications found
Genes affected
CREBBP (HGNC:2348): (CREB binding protein) This gene is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. First isolated as a nuclear protein that binds to cAMP-response element binding protein (CREB), this gene is now known to play critical roles in embryonic development, growth control, and homeostasis by coupling chromatin remodeling to transcription factor recognition. The protein encoded by this gene has intrinsic histone acetyltransferase activity and also acts as a scaffold to stabilize additional protein interactions with the transcription complex. This protein acetylates both histone and non-histone proteins. This protein shares regions of very high sequence similarity with protein p300 in its bromodomain, cysteine-histidine-rich regions, and histone acetyltransferase domain. Mutations in this gene cause Rubinstein-Taybi syndrome (RTS). Chromosomal translocations involving this gene have been associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2009]
CREBBP Gene-Disease associations (from GenCC):
- Rubinstein-Taybi syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
- Rubinstein-Taybi syndrome due to CREBBP mutationsInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- Menke-Hennekam syndrome 1Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 13 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004380.3
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_004380.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 16-3731322-AAGG-A is Pathogenic according to our data. Variant chr16-3731322-AAGG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 158384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004380.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CREBBP | NM_004380.3 | MANE Select | c.5039_5041delCCT | p.Ser1680del | disruptive_inframe_deletion | Exon 30 of 31 | NP_004371.2 | ||
| CREBBP | NM_001079846.1 | c.4925_4927delCCT | p.Ser1642del | disruptive_inframe_deletion | Exon 29 of 30 | NP_001073315.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CREBBP | ENST00000262367.10 | TSL:1 MANE Select | c.5039_5041delCCT | p.Ser1680del | disruptive_inframe_deletion | Exon 30 of 31 | ENSP00000262367.5 | ||
| CREBBP | ENST00000382070.7 | TSL:1 | c.4925_4927delCCT | p.Ser1642del | disruptive_inframe_deletion | Exon 29 of 30 | ENSP00000371502.3 | ||
| CREBBP | ENST00000637492.1 | TSL:5 | c.-77_-75delCCT | upstream_gene | N/A | ENSP00000490244.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461804Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727194
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1461804
Hom.:
AF XY:
AC XY:
0
AN XY:
727194
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39698
South Asian (SAS)
AF:
AC:
0
AN:
86234
European-Finnish (FIN)
AF:
AC:
0
AN:
53402
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111990
Other (OTH)
AF:
AC:
0
AN:
60392
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts